Abstract 2298: Ultra-sensitive tumor-informed ctDNA assay predicts survival in advanced melanoma patients treated with immune checkpoint inhibition
Authors: Laura Keller, Isabel Heidrich, Julian Kött, Charles W. Abbott, Sean Boyle, Jason Pugh, Richard O. Chen, Glen Geidel, Simon Ronald, Stephan W. Schneider, Christoffer Gebhardt, Klaus Pantel
Journal: Cancer Research (2023)

Abstract Introduction: Immune checkpoint inhibition (ICI) elicits clinical benefit in a subset of cancer patients and monitoring of ctDNA in peripheral blood might improve our ability to predict responses or resistance earlier than imaging. Here, we analyzed melanoma patients receiving ICI over several years using a novel tumor-informed ctDNA platform, and correlated the findings to clinical outcome. Methods: Plasma from 23 advanced melanoma patients was collected at ICI treatment cycles for up to 1,200 days and retrospectively profiled using NeXT Personal™ in this research study. NeXT Personal is a tumor-informed liquid biopsy assay that leverages whole-genome sequencing of tumor/normal samples to generate a personalized liquid biopsy panel for each patient consisting of up to 1,800 selected variants to enable ultra-sensitive molecular residual disease (MRD) detection down to 1-3 parts per million (PPM). Each bespoke panel also covers a fixed set of &amp;gt;2,100 known clinical and resistance loci for detecting variants emerging under therapeutic pressure. We compared NeXT Personal results with imaging and RECIST assessments for each patient. Results: Results showed ultra-high sensitivity for ctDNA with a wide dynamic range of detections from approximately 100,000 PPM down to 2.3 PPM. The median limit of detection was 1.97 PPM. Excluding patients with recent second-line therapy, 94% (17/18) of baseline samples were ctDNA positive (ctDNA+), including all patients who progressed. 37% (22/59) of on-treatment ctDNA+ detections were &amp;lt;100 PPM. 100% of ctDNA+ detections had correlated imaging findings via RECIST confirming presence of tumor, including the lowest PPM detections. Similarly, 100% of complete responses (CR) assessed via RECIST were ctDNA negative for all corresponding plasma timepoints. ctDNA clearance preceded imaging derived CR by an average of 81 days (clearance = 131 days, CR = 212 days). Patients that attained ctDNA clearance at one or more plasma timepoints had significantly longer overall survival (OS) (log-rank test; p = 0.007). Patients with increasing ctDNA levels over the first 25 (or 50) days compared to baseline had significantly reduced OS (p &amp;lt; 0.05). Analysis of the fixed clinical portion of each bespoke panel showed dynamic variant allele frequency changes in 21 variants including therapeutic targets such as BRAF V600E. Conclusions: Advanced melanoma patients exhibit a wide range of ctDNA concentrations at the beginning and during the course of treatment. Ultra-sensitive ctDNA detection down to 2.3 PPM was achieved using the NeXT Personal platform. Most importantly, our pilot study indicates that ctDNA measurements correlated with clinical outcome. The de novo detection of emerging clinically actionable and resistance variants using NeXT Personal can potentially be used to inform treatment once validated in future studies. Citation Format: Laura Keller, Isabel Heidrich, Julian Kött, Charles W. Abbott, Sean Boyle, Jason Pugh, Richard O. Chen, Glen Geidel, Simon Ronald, Stephan W. Schneider, Christoffer Gebhardt, Klaus Pantel. Ultra-sensitive tumor-informed ctDNA assay predicts survival in advanced melanoma patients treated with immune checkpoint inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2298.